This research represents the continuation of the PPG Mechanisms of Health Effects of Exercise in Children and builds on the discoveries and progress made over the past 4 years. The epidemics of pediatric asthma and childhood obesity continue. If not treated, these conditions cause chronic and disruptive illness throughout the lives of children, lead to long-term health impairments, such as chronic lung disease in asthma and atherosclerosis in obesity, and pose an enormous burden on an already stressed healthcare infrastructure. The broad goals of the PPG are to (1) uncover key regulatory mechanisms of inflammation that link physical activity with disease pathogenesis in children suffering from chronic illnesses, specifically, asthma and obesity, and (2) implement an innovative exercise-training program and assess its impact on biological mechanisms and disease outcomes. The PPG consists of 3 interrelated Projects and 3 Cores, all designed to achieve project goals in a cost-effective manner. The novel themes of the research are: (1) genomic, epigenetic, and functional responses to exercise of key innate immune ceils, neutrophils, monocytes, and skeletal muscle are abnormal in both asthma and obesity; (2) exercise-training can attenuate and possibly reverse these abnormalities; and (3) untreated chronic inflammatory conditions like asthma and obesity early in life will adversely impact inflammatory profiles and possibly even impair muscle growth and development over the lifespan. The overall aims of Projects I and II are to determine whether 10 weeks of exercise training can (1) benefit asthmatic children with a history of exercise-induced bronchoconstriction and (2) attenuate obesity- associated endothelial damage-increasingly recognized as a major component of the pre-clinical, pediatric origin of adult atherosclerosis. Identifying cellular mechanisms of childhood disease is often unfeasible. Consequently, we designed Project III to experimentally mimic asthma (ovalbumin sensitization) and obesity (overnutrition) using murine models at developmental stages roughly equivalent to early childhood and adolescence. We will determine how inflammation during critical periods of development can be altered by exercise-training and impact the growth and development of muscle (a tissue often ignored in pediatric research) throughout the lifespan. The Administrative Core will not only coordinate internal and external review, but also take the first steps in creating a national collaboratory focused on exercise in chronic childhood diseases. The Genomic and Inflammatory Mediator Core will continue its record of pioneering accomplishments including, for example, the first publication of microRNA responses to exercise in circulating neutrophils. Finally, the Pediatric Exercise Training Core will explore new ways to integrate community-based physical activity programs and instructors with effective, theory-based, lifestyle interventions. Collectively, the PPG will promote novel preventive and adjunctive exercise therapies in children with chronic inflammation- therapies grounded in a firm understanding of biological mechanisms. PUBLIC HEALTH RELEVANCE: Exercise is necessary for healthy growth and development in children. Despite this, we have witnessed an unprecedented decline in levels of physical activity in youth over the past several decades. The epidemic of childhood obesity is but one worrisome outcome of this trend. Physical inactivity is particularly troubling for the growing number of children with chronic inflammatory diseases like asthma. Not only are sedentary children with chronic diseases at increased risk for cardiovascular disease or osteoporosis later in life, but physical inactivity can, in many cases, exacerbate the underlying disease or condition. Our goal is to better understand the role of physical activity in the challenging context of childhood disease. In this way, we hope to optimize the use of exercise as therapy even when chronic illness is present.